Place de la virothérapie dans le traitement du cancer de la vessie

Bladder cancer is the most common cancer of the urinary system and ranks fifth among all cancers in Canada with over 9000 new diagnoses each year. In 80% of cases, patients are diagnosed with non-muscle-invasive bladder cancer (NMIBC), which has a good prognosis but frequent recurrence. 20% of patients are diagnosed with musculoinvasive bladder cancer (MIBC) with a high risk of metastasis and a lower survival rate. The management of NMIBC is based on several therapeutic approaches depending on the level of risk of progression to a more aggressive state. After transurethral resection of the tumor, in low-risk cases, intravesical chemotherapy is offered and usually has good results. In high-risk NMIBC, the standard treatment is intravesical immunotherapy with BCG to reduce the risk of recurrence and tumor progression. Despite its effectiveness, BCG therapy has some limitations. Patients may develop local or systemic side effects that may lead to discontinuation of treatment. In addition, up to 40% of patients fail to respond to treatment or recur after treatment is stopped, requiring regular cystoscopy monitoring and accounting for the high cost of bladder cancer management. In recent years, CPI « Check point inhibitors » have been included in the treatment of bladder cancer after failure of BCG, but their effectiveness is limited. Patients who do not respond to these therapies will inevitably progress to a more aggressive state with bladder muscle involvement or metastasis. In these patients, the only therapeutic option is radical cystectomy, which improves survival but has an impact on patients' quality of life. It is therefore necessary to find therapeutic alternatives for these patients and one of the possibilities is the virotherapy. The advantage of using oncolytic viruses is that they specifically infect and destroy cancer cells and spare normal cells, since antiviral immunity is compromised in most cancer cells including bladder cancer cells. They are also able to replicate in the tumor microenvironment and induce an antitumor immune response. In our previous preclinical studies, we have already demonstrated that the vesicular stomatitis virus (VSVd51-GM-CSF) is effective against bladder cancer. The objective of this project is to compare the efficacy of VSVd51-GM-CSF to that of the standard treatment, BCG. To do so, we conducted in vitro experiments with murine (MB49) and human (TCCSUP, UMUC3) bladder cancer cell lines and ex vivo with samples from NMIBC patients that we treated with BCG or VSVd51-GMCSF. We compared the cytotoxicity of the virus to that of BCG by conducting cell viability assays. We characterized the ability to induce immunogenic cell death by assaying the release of DAMPs « Damage-associated molecular patterns » (ATP, HMGB1, HSP, Calreticulin) into the medium following treatment with VSVd51-GM-CSF or BCG. Finally, we compared the immune response induced by the virus to that induced by BCG. We also performed in vivo experiments with a syngeneic orthotopic model of cancer cell implantation in the bladder of mice and with a model of exposure to a carcinogen, BBN, which promotes the spontaneous development of bladder cancer, to characterize the immune response and its impact on the evolution of cancer in mice treated with the virus compared to those treated with BCG. All these experiments allowed us to demonstrate that VSVd51-GM-CSF has a higher cytotoxicity than BCG, induces a higher immunogenic cell death and leads to a more efficient activation of immune cells with a regression of the tumor volume and an improvement of the survival of mice. These translational studies demonstrate the potential of VSVd51-GM-CSF as a therapeutic agent in bladder cancer patients and could be an alternative in case of BCG treatment failure.

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